The studies we are proposing will compare epidermal growth factor receptor (EGFR) targeted liposome- formulated topotecan (EGFR-LFT) vs. non-targeted liposome-formulated topotecan (NT-LFT) for efficacy in treating orthotopic glioblastoma (GBM) xenografts. As part of this research, we will also address GBM EGFR status (EGFR-amplified vs. non-amplified) and LFT route of delivery (direct intracranial administration vs. systemic administration) as factors that influence LFT therapeutic efficacy. Liposome formulations of topotecan will be tested as single agents as well as in combination with radiation. At the end of the requested period of support, this project will address whether systemic delivery of LFT is a viable strategy for treating brain tumors, and whether EGFR targeted delivery of LFT should be specifically used for treating tumors that have amplified EGFR. More generally, this project will address whether EGFR targeting of liposome-formulated chemotherapy should be further developed for use in clinical practice of treating GBM. PUBLIC HEALTH RELEVANCE: The studies proposed in this application will determine whether a molecular characteristic in a highly malignant type of brain tumor can be exploited for improving the delivery and anti-tumor effect of a commonly used cancer therapeutic. The results of these studies will have important implications for improving the delivery and efficacy of a large number of anti-cancer agents.